Combination therapy including 9-nitro-20(S)-camptothecin and 5-fluorouracil

ABSTRACT

A method for treating diseases comprises delivering to a patient in need of treatment a therapeutically effective amount of 20(S)-camptothecin, an analog of 20(S)-camptothecin, or a derivative of 20(S)-camptothecin in combination with an effective amount of at least one of an alkylating agent, epidophyllotoxin, antimetabolite, antibiotic or vinca alkaloid.

FIELD OF THE INVENTION

[0001] This invention relates to a method for treating disease using acamptothecin, and more specifically a method for treating disease usinga camptothecin in combination with another drug.

DESCRIPTION OF RELATED ART

[0002] 20(S)-camptothecin, a plant alkaloid, was found to haveanticancer activity in the late 1950's. Wall, M. et al., Plant antitumoragents. I. The isolation and structure of camptothecin, a novelalkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J.Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al.,Camptothecin: Discovery to Clinic, 803 Annals of the New York Academy ofSciences 1 (1996). These documents, and all documents (articles patents,etc.) cited to herein, are incorporated by reference into thespecification as if reproduced fully below. The chemical formula ofcamptothecin was determined to be C₂₀H₁₆N₂O₄.

[0003] 20(S)-camptothecin itself is insoluble in water. However, duringthe sixties and seventies the sodium salt of 20(S)-camptothecin wasderived from 20(S)-camptothecin through opening of the lactone ringusing a mild base. Clinical trials were then conducted using thishydrosoluble. sodium salt derivative of 20(S)-camptothecin(20(S)-camptothecin Na+), which was administered intravenously. Thestudies were later abandoned because of the high toxicity and lowpotency of 20(S)-camptothecin Na⁺. Gottlieb, J. A., et al., Preliminarypharmacological and clinical evaluation of camptothecin sodium salt (NSC100880): Cancer Chemother. Rep. 54:461-470 (1979); Muggia, F. M., etal., Phase I clinical trials of weekly and daily treatment withcamptothecin (NSC 100880): Correlation with clinical studies, CancerChemother. Rep. 56:515-521 (1972); Gottlieb, J. A. et al., Treatment ofmalignant melanoma with camptothecin (NSC 100880), Cancer Chemother.Rep. 56:103-105 (1972); and Moertel, C. G., et al., Phase II study ofcamptothecin (NSC 100880) in the treatment of advanced gastrointestinalcancer, Cancer Chemother Rep. 56:95-101 (1972).

[0004] Despite its potential, interest in 20(S)-camptothecin as atherapeutic remained at a low ebb until the mid-1980's. By that time,drug therapies were being evaluated for treating human cancer usinghuman cancer xenograft lines. During these evaluations, human tumors areserially heterotransplanted into immunodeficient, so-called “nude” mice,and the mice then tested for their responsiveness to a specific drug.(Giovanella, B. C., et al., Cancer 52(7): 1146 (1983)). The dataobtained in these studies strongly support the validity ofheterotransplanted human tumors into immunodeficient mammals, such asnude mice, as a predictive model for testing the effectiveness ofanticancer agents.

[0005] 20(S)-camptothecin, and later some of its substituted forms,elicited differential responses in the cell cycle of nontumorigenic andtumorigenic human cells in vitro. Although it is not yet understood why20(S)-camptothecin and some of its substituted forms are cytostatic fornontumorigenic cells and cytotoxic for tumorigenic cells, the selectivetoxicity of the compounds against tumorigenic cells in vitro and in vivowas an especially interesting feature of these drugs.

[0006] Investigators began to experiment with various substituted formsof 20(S)-camptothecin. Good activity was found when varioussubstitutions were made to the 20(S)-camptothecin scaffold. For example,9-Amino-20(S)-Camptothecin (9AC) and10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of havinghigh anticancer activity against human colon cancer xenografts.Giovanella, B. C., et al., Highly effective topoisomerase-I targetedchemotherapy of human colon cancer in xenografts, Science 246:1046-1048(1989).

[0007] Additionally, 9-nitrocamptothecin (9NC) has shown high activityagainst human tumor xenograft models. 9NC has a nine position hydrogensubstituted with a nitro moiety. 9NC has inhibited the growth of humantumor xenografts in immunodeficient nude mice and has induced regressionof human tumors established as xenografts in nude mice with little or noappearance of any measurable toxicity. D. Chatterjee et al., Inductionof Apoptosis in Malianant and Camptothecin-resistant Human Cells, 803Annals of the New York Academy of Sciences 143 (1996).

[0008] U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed methods oftreating specific forms of cancer with water-insoluble 20(S)camptothecinand derivatives thereof, having the closed-lactone ring intact. Inparticular, transdermal, oral and intramuscular methods ofadministration using solutions of water-insoluble 20(S)-camptothecinwere disclosed.

[0009] Other substituted 20(S)-camptothecin compounds that have shownpromise include 7-ethyl-10-hydroxy 20(S)-camptothecin, and other7,9,10,11-substituted compounds.

[0010] A continuing need exists to develop new and improved ways toexploit the useful therapeutic activities of 20(S)-camptothecin and itsvarious derivatives and analogs.

SUMMARY OF THE INVENTION

[0011] The present invention relates to new and improved compositions.kits. and methods for treating diseases using a combination therapywhich includes 20(S)-camptothecin, an analog or 20(S)-camptothecin, or aderivative of 20(S)-camptothecin, collectively referred to herein asCPT. A therapeutic agent which exhibits a therapeutic synergistic effectwith CPT is employed in the therapy.

[0012] A wide variety of non-CPT therapeutic agents with therapeuticsynergistic effects with CPT may be employed. Examples of such non-CPTtherapeutic agents include, but are not limited to alkylating agents.epidophyllotoxins, antimetabolites, antibiotics, and vinca alkaloids.Examples of alkylating agents include, but are not limited tocyclophosphamide, ifosfamide, melphalan, hexamethylmelamine, thiotepaand dacarbazine. Examples of antimetabolites include, but are notlimited to 5-fluorouracil, cytarabine and folic acid analogs. Examplesof folic acid analogs include, but are not limited to methotrexate,idatrexate or trimetrexate. Examples of antibiotics include, but are notlimited to daunorubicine, doxorubicin, bleomycin or mitomycin. Examplesof vinca alkaloids include, but are not limited to vinblastine,vincristine, and their synthetic analogues. Examples of epidophyllotoxininclude, but are not limited to etoposide and teniposide.

[0013] The method may be used to treat a wide variety of diseases forwhich CPT has therapeutic activity. In one embodiment, the combinationtherapy methods and compositions of the present invention are useful inthe treatment of neoplastic diseases.

DETAILED DESCRIPTION OF THE INVENTION

[0014] 1. Camptothecin Compounds (CPT)

[0015] The class of camptothecin compounds referred to herein as CPTinclude various 20(S)-camptothecins, analogs of 20(S)camptothecin. andderivatives of 20(S)-camptothecin. Camptothecin. when used in thecontext of this invention, includes the plant alkaloid20(S)-camptothecin, both substituted and unsubstituted camptothecins,and analogs thereof. Examples of camptothecin derivatives include, butare not limited to, 9-nitro-20(S)-camptothecin,9-amino-20(S)-camptothecin, 9-methyl-camptothecin, 9-chlorocamptothecin,9-flouro-camptothecin, 7-ethyl camptothecin, 10-methylcamptothecin,10-chloro—camptothecin, 10-bromo-camptothecin, 10-fluoro-camptothecin,9-methoxy-camptothecin, 11-fluoro-camptothecin, 7-ethyl-10-hydroxycamptothecin, 10,11-methylenedioxy camptothecin, and 10,11-ethylenedioxycamptothecin, and 7-(4-methylpiperazinomethylene)-10,11-methylenedioxycamptothecin. Prodrugs of camptothecin include, but are not limited to,esterified camptothecin derivatives as decribed in U.S. Pat. No.5,731,316, such as camptothecin 20-O-propionate, camptothecin20-O-butyrate, camptothecin 20-O-valerate, camptothecin 20-O-heptanoate,camptothecin 20-O-nonanoate, camptothecin 20-O-crotonate, camptothecin20-O-2′,3′-epoxy-butyrate, nitrocamptothecin 20-O-acetate,nitrocamptothecin 20-O-propionate, and nitrocamptothecin 20-O-butyrate.

[0016] In particular, when substituted camptothecins are used, a largerange of substitutions may be made to the camptothecin scaffold, whilestill retaining activity. In a preferable embodiment, the camptothecinscaffold is substituted at the 7, 9, 10, 11, and/or 12 positions. Suchpreferable substitutions may serve to provide differential activitiesover the unsubstituted camptothecin compound. Especially preferable are9-nitrocamptothecin, 9-aminocamptothecin,10,11-methylendioxy-20(S)-camptothecin, topotecan, irinotecan,7-ethyl-10-hydroxy camptothecin, or another substituted camptothecinthat is substituted at least one of the 7, 9, 10, 11, or 12 positions.

[0017] Native, unsubstituted, camptothecin can be obtained bypurification of the natural extract, or may be obtained from the StehlinFoundation for Cancer Research (Houston, Tex.). Substitutedcamptothecins can be obtained using methods known in the literature, orcan be obtained from commercial suppliers. For example,9-nitrocamptothecin may be obtained from SuperGen, Inc. (San Ramon,Calif.), and 9-aminocamptothecin may be obtained from IdecPharmaceuticals (San Diego, Calif.). Camptothecin and various of itsanalogs may also be obtained from standard fine chemical supply houses,such as Sigma Chemicals.

[0018] Particular examples of 20(S)-camptothecins include9-nitrocamptothecin, 9-aminocamptothecin,10,11-methylendioxy-20(S)-camptothecin, topotecan, irinotecan,7-ethyl-10-hydroxy camptothecin, or another substituted camptothecinthat is substituted at least one of the 7, 9, 10, 11, or 12 positions.These camptothecins may optionally be substituted.

[0019] 2. Non-CPT Therapeutic Agents

[0020] A wide variety non-CPT therapeutic agents may have a therapeuticsynergistic effect with CPT. Examples of such non-CPT therapeutic agentsinclude but are not limited to alkylating agents, epidophyllotoxins,antimetabolites, and vinca alkaloids. Examples of alkylating agentsinclude, but are not limited to cyclophosphamide, diethylnitroamine,ifosfamide, melphalan. hexamethylmelamine, thiotepa and dacarbazine.Examples of antimetabolites include, but are not limited to5-fluorouracil, cytarabine and folic acid analogs. Examples of folicacid analogs include, but are not limited to methotrexate, idatrexate ortrimetrexate. Examples of antibiotics include, but are not limited todaunorubicine, doxorubicin, bleomycin or mitomycin. Examples of vincaalkaloids include. but are not limited to vinblastine, vincristine, andtheir synthetic analogues. Examples of epidophyllotoxin include, but arenot limited to etoposide and teniposide.

[0021] 3. Indications for Combination Therapy

[0022] Preferable indications that may be treated using the combinationtherapies of the present invention include those involving undesirableor uncontrolled cell proliferation. Such indications include restenosis,benign tumors, a various types of cancers such as primary tumors andtumor metastasis, abnormal stimulation of endothelial cells(atherosclerosis), insults to body tissue due to surgery, abnormal woundhealing, abnormal angiogenesis, diseases that produce fibrosis oftissue, repetitive motion disorders, disorders of tissues that are nothighly vascularized, and proliferative responses associated with organtransplants.

[0023] Specific types of restenotic lesions that can be treated usingthe present invention include coronary, carotid, and cerebral lesions.Specific types of benign tumors that can be treated using the presentinvention include hemangiomas, acoustic neuromas, neurofibroma.trachomas and pyogenic granulomas. Specific types of cancers that can betreated using this invention include acute myelogenous leukemia,bladder, breast, cervical, cholangiocarcinoma, chronic myelogenousleukemia, colorectal, gastric sarcoma, glioma, leukemia, lung, lymphoma,melanoma, multiple myeloma, osteosarcoma, ovarian, pancreatic,prostrate, stomach, or tumors at localized sites including inoperabletumors or in tumors where localized treatment of tumors would bebeneficial, and solid tumors. In a more preferable embodiment, the typesof cancer include pancreatic, and/or colorectal. Treatment of cellproliferation due to insults to body tissue during surgery may bepossible for a variety of surgical procedures, including joint surgery,bowel surgery, and cheloid scarring. Diseases that produce fibrotictissue include emphysema. Repetitive motion disorders that may betreated using the present invention include carpal tunnel syndrome. Anexample of cell proliferative disorders that may be treated using theinvention is a bone tumor.

[0024] Abnormal angiogenesis that may be may be treated using thisinvention include those abnormal angiogenesis accompanying rheumatoidarthritis, psoriasis, diabetic retinopaphy, and other ocular angiogenicdiseases such as retinopathy of prematurity (retrolental fibropiastic),macular degeneration, corneal graft rejection, neuroscular glaucoma andOster Webber syndrome.

[0025] The proliferative responses associated with organ transplantationthat may be treated using this invention include those proliferativeresponses contributing to potential organ rejections or associatedcomplications. Specifically, these proliferative responses may occurduring transplantation of the heart, lung, liver, kidney, and other bodyorgans or organ systems.

[0026] 4. Compositions, Formulations, and Kits

[0027] Compositions according to the present invention might include aCPT, a non-CPT therapeutic agent, together with a pharmaceuticalexcipient. The composition preferably have a therapeutic synergy in thetreatment of a disease, or a synergistic effect on the subjected beingtreated. As used herein, a synergistic effect is achieved when a greatertherapeutic effect results with a combination therapy than using eitherdrug or monotherapy alone. One advantage of combination therapy with asynergistic effect is that lower dosages of one or both of the drugs ortherapies may be used so that the therapeutic index is increased andtoxic side effects are reduced.

[0028] In an aspect, the invention is directed to kits comprising acontainer that contains the compound. In another aspect, the inventionis directed to the kits, wherein the camptothecin is9-nitrocamptothecin, or 9-aminocamptothecin. In still another aspect,the invention is directed to the kits, wherein the lactone ringprotecting moiety is a polyalkylene oxide, dextran, polyvinyl alcohol,carbohydrate polymer, an antibody, streptozoticin or derivatives ormixtures thereof.

[0029] In still another aspect, the invention is directed to the kits,wherein the polyalkylene oxide is a polyethylene glycol.

[0030] In still another aspect, the invention is directed to kitscomprising a container that contains the composition. In still anotheraspect, the invention is directed to the kits, wherein the camptothecinis 9-nitrocamptothecin, or 9-aminocamptothecin. In another aspect, theinvention is directed to the kits, wherein the lactone ring protectingmoiety is a polyalkylene oxide, dextran, polyvinyl alcohol, carbohydratepolymer, an antibody, streptozoticin or derivatives or mixtures thereof.

[0031] In still another aspect, the invention is directed to the kits,wherein the polyalkylene oxide is a polyethylene glycol.

[0032] 5. Delivery of Therapeutic Agents

[0033] A wide variety of delivery methods and formulations for differentdelivery methods are intended to be encompassed by the combinationtherapies of the present invention.

[0034] The inventive combination of therapeutic agents may beadministered as compositions that comprise the inventive combination oftherapeutic agents. Such compositions may include, in addition to theinventive combination of therapeutic agents. conventional pharmaceuticalexcipients, and other conventional, pharmaceutically inactive agents.Additionally, the compositions may include active agents in addition tothe inventive combination of therapeutic agents. These additional activeagents may include additional compounds according to the invention, orone or more other pharmaceutically active agents. In preferableembodiments, the inventive compositions will contain the active agents,including the inventive combination of therapeutic agents, in an amounteffective to treat an indication of interest.

[0035] The inventive combination of therapeutic agents and/orcompositions may be administered or coadministered orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compoundsand/or compositions according to the invention may also be administeredor coadministered in slow release dosage forms.

[0036] The inventive combination of therapeutic agents and compositionsmay be administered by a variety of routes, and may be administered orcoadministered in any conventional dosage form. Coadministration in thecontext of this invention is defined to mean the administration of morethan one therapeutic in the course of a coordinated treatment to achievean improved clinical outcome. Such coadministration may also becoextensive, that is, occurring during overlapping periods of time.

[0037] One therapeutically interesting route of administration orcoadministration is local delivery. Local delivery of inhibitory amountsof inventive combination of therapeutic agents and/or compositions canbe by a variety of techniques and structures that administer theinventive combination of therapeutic agents and/or compositions at ornear a desired site. Examples of local delivery techniques andstructures are not intended to be limiting but rather as illustrative ofthe techniques and structures available. Examples include local deliverycatheters, site specific carriers, implants. direct injection, or directapplications.

[0038] Local delivery by a catheter allows the administration of ainventive combination of therapeutic agents and/or compositions directlyto the desired site. Examples of local delivery using a balloon catheterare described in EP 383 492 A2 and U.S. Pat. No. 4,636,195 to Wolinsky.Additional examples of local. catheter-based techniques and structuresare disclosed in U.S. Pat. No. 5,049,132 to Shaffer et al. and U.S. Pat.No. 5,286,254 to Shapland et al.

[0039] Generally, the catheter must be placed such that the inventivecombination of therapeutic agents s and/or compositions can be deliveredat or near the desired site. Dosages delivered through the catheter canvary, according to determinations made by one of skill, but often are inamounts effective to create a cytotoxic or cytostatic effect at thedesired site. Preferably, these total amounts are less than the totalamounts for systemic administration of the inventive combination oftherapeutic agents and/or compositions, and are less than the maximumtolerated dose. The inventive combination of therapeutic agents s and/orcompositions delivered through catheters preferably should be formulatedto a viscosity that enables delivery through a small treatment catheter,and may be formulated with pharmaceutically acceptable additionalingredients (active and inactive).

[0040] Local delivery by an implant describes the placement of a matrixthat contains the inventive combination of therapeutic agents s and/orcompositions into the desired site. The implant may be deposited bysurgery or other means. The implanted matrix releases the inventivecombination of therapeutic agents s and/or compositions by diffusion,chemical reaction, solvent activators, or other equivalent mechanisms.Examples are set forth in Lange, Science 249:1527-1533 (September,1990). Often the implants may be in a form that releases the inventivecombination of therapeutic agents s and/or compositions over time; theseimplants are termed time-release implants. The material of constructionfor the implants will vary according to the nature of the implant andthe specific use to which it will be put. For example, biostableimplants may have a rigid or semi-rigid support structure, withinventive combination of therapeutic agents and/or composition deliverytaking place through a coating or a porous support structure. Otherimplants made be made of a liquid that stiffens after being implanted ormay be made of a gel. The amounts of inventive combination oftherapeutic agents and/or composition present in or on the implant maybe in an amount effective to treat cell proliferation generally, or aspecific proliferation indication, such as the indications discussedherein.

[0041] One example of local delivery of the inventive combination oftherapeutic agents and/or composition by an implant is use of abiostable or bioabsorbable plug or patch or similar geometry that candeliver the inventive combination of therapeutic agents and/orcomposition once placed in or near the desired site. An example of suchimplants can be found in U.S. Pat. No. 5,429,634 to Narciso, Jr.

[0042] A particular application of use of an implant according to theinvention is treatment of cell proliferation in tissue that is nothighly vascularized, as discussed briefly above. An example of suchtissue is bone tissue. The difficulty in treating uncontrolledproliferative cell growth in bone tissue may be exemplified by thedifficulties in treating bone tumors. Such tumors are typicallyrefractory to treatment, in part because bone tissue is not highlyvascularized. An implant in or near the proliferative site maypotentially have localized cytotoxic or cytostatic effects with regardto the proliferative site. Therefore, in one embodiment, the inventionmay be used to treat bone tumors.

[0043] Another example of local delivery by an implant is the use of astent. Stents are designed to mechanically prevent the collapse andreocclusion of the coronary arteries. Incorporating an inventivecombination of therapeutic agents and/or composition into the stent maydeliver the agent directly to or near the proliferative site. Certainaspects of local delivery by such techniques and structures aredescribed in Kohn, Pharmaceutical Technology (October, 1990). Stents maybe coated with the inventive combination of therapeutic agents and/orcomposition to be delivered. Examples of such techniques and structuresmay be found in U.S. Pat. No. 5,464,650 to Berg et al., U.S. Pat. No.5,545,208 to Wolff et al., U.S. Pat. No. 5,649,977 to Campbell, U.S.Pat. No. 5,679,400 to Tuch, EP 0 716 836 to Tartaglia et al.Alternatively, the inventive combination of therapeutic agents and/orcomposition loaded stent may be biorotable, i.e. designed to dissolve,thus releasing the inventive combination of therapeutic agents and/orcomposition in or near the desired site, as disclosed in U.S. Pat. No.5,527,337 to Stack et al. The present invention can be used with a widevariety of stent configurations, including, but not limited to shapememory alloy stents, expandable stents, and stents formed in situ.

[0044] Amounts of the inventive combination of therapeutic agents and/orcomposition delivered by the stent can vary, according to determinationsmade by one of skill, but preferably are in amounts effective to createa cytotoxic or cytostatic effect at the desired site. Preferably, thesetotal amounts are less than the total amounts for systemicadministration of the inventive combination of therapeutic agents and/orcomposition, and are preferably less than the maximum tolerated dose.Appropriate release times can vary, but preferably should last fromabout 1 hour to about 6 months, most preferably from about 1 week toabout 4 weeks. Formulations including the inventive combination oftherapeutic agents and/or composition for delivery of the agent via thestent can vary, as determinable by one of skill, according to theparticular situation, and as generally taught herein.

[0045] Another example is a delivery system in which a polymer thatcontains the inventive combination of therapeutic agents and/orcomposition is injected into the target cells in liquid form. Thepolymer then cures to form the implant in situ. One variation of thistechnique and structure is described in WO 90/03768 to Donn.

[0046] Another example is the delivery of the inventive combination oftherapeutic agents and/or composition by polymeric endoluminal sealing.This technique and structure uses a catheter to apply a polymericimplant to the interior surface of the lumen. The inventive combinationof therapeutic agents and/or composition incorporated into thebiodegradable polymer implant is thereby released at the desired site.One example of this technique and structure is described in WO 90/01969to Schindler.

[0047] Another example of local delivery by an implant is by directinjection of vesicles or microparticulates into the desired site. Thesemicroparticulates may comprise substances such as proteins, lipids,carbohydrates or synthetic polymers. These microparticulates have theinventive combination of therapeutic agents and/or compositionincorporated throughout the microparticle or over the microparticle as acoating. Examples of delivery systems incorporating microparticulatesare described in Lange, Science, 249:1527-1533 (September, 1990) andMathiowitz, et al., J. App. Poly Sci. 26:809 (1981).

[0048] Local delivery by site specific carriers describes attaching theinventive combination of therapeutic agents and/or composition to acarrier which will direct the drug to the desired site. Examples of thisdelivery technique and structure include the use of carriers such as aprotein ligand or a monoclonal antibody. Certain aspects of thesetechniques and structures are described in Lange, Science 249:1527-1533.

[0049] Local delivery also includes the use of topical applications. Anexample of a local delivery by topical application is applying theinventive combination of therapeutic agents and/or composition directlyto an arterial bypass graft during a surgical procedure. Otherequivalent examples will no doubt occur to one of skill in the art.

[0050] The inventive combination of therapeutic agents s and/orcompositions may be used in the form of kits. The arrangement andconstruction of such kits is conventionally known to one of skill in theart. Such kits may include containers for containing the inventivecombination of therapeutic agents s and/or compositions, and/or otherapparatus for administering the inventive combination of therapeuticagents and/or compositions.

[0051] It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

What is claimed is:
 1. A pharmaceutical composition having therapeuticsynergy comprising: 20(S)-camptothecin, an analog of 20(S)-camptothecin,or a derivative of 20(S)-camptothecin; and at least one of an alkylatingagent, epidophyllotoxin, antimetabolite, antibiotic or vinca alkaloid.2. A pharmaceutical composition according to claim 1, wherein thealkylating agent is cyclophosphamide, ifosfamide, melphalan,hexamethylmelamine, thiotepa or dacarbazine.
 3. A pharmaceuticalcomposition according to claim 1, wherein the antimetabolite is5-fluorouracil, cytarabine or a folic acid analog.
 4. A pharmaceuticalcomposition according to claim 1, wherein the antibiotic isdaunorubicine, doxorubicin, bleomycin or mitomycin.
 5. A pharmaceuticalcomposition according to claim 1, wherein the vinca alkaloid isvinblastine, vincristine, or their synthetic analogues.
 6. Apharmaceutical composition according to claim 1, wherein theepidophyllotoxin is etoposide or teniposide.
 7. A pharmaceuticalcomposition according to claim 1, wherein said composition is useful inthe treatment of neoplastic diseases.
 8. A pharmaceutical compositionaccording to claim 1, wherein the 20(S)-camptothecin is9-amino-20(S)-camptothecin.
 9. A pharmaceutical composition according toclaim 1, wherein the 20(S)-camptothecin is 9-nitro-20(S)-camptothecin.10. A method for treating disease comprising: delivering to a patient inneed of treatment a therapeutically effective amount of20(S)-camptothecin, an analog of 20(S)-camptothecin, or a derivative of20(S)-camptothecin in combination with an effective amount of at leastone of an alkylating agent, epidophyllotoxin, antimetabolite, antibioticor vinca alkaloid.
 11. A method according to claim 10, wherein thealkylating agent is cyclophosphamide, ifosfamide, melphalan,hexamethylmelamine, thiotepa or dacarbazine.
 12. A method according toclaim 10, wherein the antimetabolite is 5-fluorouracil, cytarabine or afolic acid analog.
 13. A method according to claim 10, wherein theantibiotic is daunorubicine, doxorubicin, bleomycin or mitomycin.
 14. Amethod according to claim 10, wherein the vinca alkaloid is vinblastine,vincristine, or their synthetic analogues.
 15. A method according toclaim 10, wherein the epidophyllotoxin is etoposide or teniposide.
 16. Amethod according to claim 10, wherein said composition is useful in thetreatment of neoplastic diseases.
 17. A method according to claim 10.wherein the 20(S)-camptothecin is 9-amino-20(S)-camptothecin.
 18. Amethod according to claim 10, wherein the 20(S)-camptothecin is9-nitro-20(S)-camptothecin.